Background/Objectives: Neuroendocrine tumors (NETs) can arise in any organ and are most commonly found in the lungs and gastroenteropancreatic (GEP) system. GEP-NETs represent a small percentage of gastrointestinal cancers, and therefore, the standard treatment is not well-defined, especially for advanced disease. Our objective is to review GI NETs among veterans and analyze their therapeutic outcomes. Methods: A total of 61 GI NET cases were identified from our institution from 2019-2024. In total, twenty-seven review papers, ten population-based/multicenter/outcome studies, six case reports, and one case series were reviewed for the literature review. Results: The incidence of GI NETs at our institution was higher than the known epidemiology of GI NETs. Small intestine NETs were one of the most common sites of GEP-NETs at our institution, with only one of nineteen cases being grade 3 poorly differentiated neuroendocrine carcinoma. All cases of colonic and rectal NETs had good clinical outcomes consistent with findings from the literature. Most of the gastric NETs were type 1 and had benign courses of disease, except for one case with an intermediate grade and metastatic liver lesions. One case of esophageal neuroendocrine carcinoma (E-NEC) showed a complete response to chemotherapy despite a significant tumor burden on presentation and high-grade pathology, while another case of ENEC had recurrent disease despite systemic therapy. Conclusions: While the role of surgery or endoscopic resection is limited to localized tumors, combined treatment with chemoradiation can significantly improve patient outcomes, especially in high-grade, poorly differentiated tumors. Further studies are needed to establish systemic (i.e., chemotherapy and radiation) treatment strategies for poorly differentiated GI NETs.

Rectal neuroendocrine tumors (NET) are thought to originate from the diffuse neuroendocrine system. The lack of apparent signs of illness and the patient's non-specific presentations often cause a delay in diagnosis, until in their final stages of cancer. Thus, rectal NETs pose a significant challenge to most physicians.

This article presents three cases of rectal NETs discovered during anorectal surgery. Owing to their atypical symptoms, they were initially diagnosed as mixed hemorrhoids or perianal fistulas. However, the patients were diagnosed with rectal NETs and thus underwent endoscopic dissection or transanal endoscopic microsurgery. Histological analysis revealed three rectal NETs, one G1 and two G2. All patients were followed-up for more than 6 months, with excellent outcomes without recurrence.

The etiology, pathogenesis, therapeutic methods, prevention, and prognosis of rectal NETs remain challenging. Given the variable understanding of the most appropriate operative approaches for rectal NETs, our objective was to broaden the perspective of this infrequent disease by delivering distinctive individual experiences and emphasizing the therapeutic significance of delicate surgery.

The clinical utility of applying endoscopic vascular patterns in rectal neuroendocrine tumor (NET) remains unknown. The aims of this study were to develop a system for utilizing vascular patterns for tumor grade and submucosal invasion depth.

We retrospectively included patients diagnosed as well-differentiated rectal NET between March 2015 and February 2024. The entire dataset was divided into evaluation and validation sets. In the evaluation set, the relationship between endoscopic tumor features and tumor grade was explored using a multivariable regression model. Based on the endoscopic vessel characteristics, vascular patterns were established and classified into V1 and V2 types. In the validation set, 104 lesions were used to assess the diagnostic performance of the vascular patterns.

Multivariate analysis demonstrated good association between tumor grade and vascular pattern (13.65 odds ratio; 95 % confidence interval, 2.06-90.58). Vascular patterns exhibited almost perfect inter- and intra-observer agreement (kappa = 0.957). The sensitivity, positive predictive value and accuracy of V1 for predicting grade 1 were 94.5 %, 97.7 and 93.3 %, respectively. Histopathological analysis revealed significantly deeper submucosal invasion depth for V2 than that for V1 lesions (p < 0.001).

Vascular patterns can help identify tumor grade and assess submucosal invasion depth.

Rectal neuroendocrine neoplasms pose significant challenges due to their varied presentations and prognoses. Traditional prognostic models, while useful, often fall short of accurately predicting clinical outcomes for these patients. This article discusses the development and implications of a novel prognostic tool, the GATIS score, which aims to enhance predictive accuracy and guide treatment strategies more effectively than current methods. Utilizing data from a large cohort and employing sophisticated statistical models, the GATIS score integrates clinical and pathological markers to provide a nuanced assessment of prognosis. We evaluate the potential of this score to transform clinical decision-making processes, its integration into current medical practices, and future directions for its development. The integration of genetic markers and other biomarkers could further refine its predictive power, highlighting the ongoing need for innovation in the management of rectal neuroendocrine neoplasms.

A 65-year-old male presented after a positive Cologuard testing. He was asymptomatic at presentation, with no reported complaints of fever, chills, abdominal pain, diarrhea, constipation, hematochezia, or unexpected weight loss. CT imaging of the abdomen and pelvis revealed a 2 cm mass at the rectosigmoid junction with a single enlarged lymph node nearby measuring 2.7 x 1.6 cm, raising suspicion for regional metastatic adenopathy. He underwent a colonoscopy, which confirmed a rectosigmoid mass. Biopsy results showed adenocarcinoma of the colon. Consequently, the patient was scheduled for a laparoscopic sigmoidectomy with low anterior resection. The pathology of the surgical specimen confirmed adenocarcinoma, moderately differentiated, associated with a component of poorly differentiated large cell neuroendocrine carcinoma, with the neuroendocrine component best developed in the lymph node metastasis. Although the patient did not meet the standard criteria for mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN) tumors, treatment was administered using chemotherapeutic agents typically reserved for MiNENs. He was treated with platinum-based doublet with good response and has been in remission for one and a half years. This report highlights the importance of flexible therapeutic approaches when pathology marginally deviates from the standard established criteria, illustrating that tailoring treatment to the specific pathology can provide considerable patient benefits.

Lateral pelvic lymph node (LPLN) metastasis of rectal neuroendocrine tumors (NETs) is rare, with unknown oncological features. We investigated the oncological impact of LPLN metastasis in patients with rectal NETs.

This study included 214 patients with rectal NETs who underwent curative surgery. We evaluated their clinicopathological characteristics and short- and long-term outcomes.

LPLN dissection was performed in 15 patients with LPLN swelling ≥ 7 mm (preoperative imaging); 12 patients had LPLN metastases, 6 of whom had LPLN metastases without mesorectal lymph node metastases (skip metastasis). The short-term outcomes were similar between the groups with and without LPLN dissection. The median follow-up period was 59.4 months, and patients with LPLN metastasis showed significantly shorter disease-free and overall survival rates than those without metastasis. Among 199 patients who did not undergo LPLN dissection, only 1 had LPLN recurrence. In a univariate analysis, tumor depth, tumor grade, and LPLN metastasis were associated with the overall survival. In the multivariate analysis, only LPLN metastasis was an independent predictor of the overall survival.

LPLN metastasis is a poor prognostic factor for patients with rectal NETs. LPLN enlargement can be considered an indication for dissection, owing to its high rate of metastasis and associated poor prognosis.

In recent years, the incidence of patients with colorectal neuroendocrine neoplasms (CRNENs) has been continuously increasing. When diagnosed, most patients have distant metastases. Liver metastasis (LM) is the most common type of distant metastasis, and the prognosis is poor once it occurs. However, there is still a lack of large studies on the risk and prognosis of LM in CRNENs. This study aims to identify factors related to LM and prognosis and to develop a predictive model accordingly.

In this study, the Surveillance, Epidemiology, and End Results (SEER) database was used to collect clinical data from patients with CRNENs. The logistic regression analyses were conducted to identify factors associated with LM in patients with CRNENs. The patients with LM formed the prognostic cohort, and Cox regression analyses were performed to evaluate prognostic factors in patients with liver metastasis of colorectal neuroendocrine neoplasms (LM-CRNENs). Predictive and prognostic nomogram models were constructed based on the multivariate logistic and Cox analysis results. Finally, the capabilities of the nomogram models were verified through model assessment metrics, including the receiver operating characteristic (ROC) curves, calibration curve, and decision curve analysis (DCA) curve.

This study ultimately encompassed a total of 10,260 patients with CRNENs. Among these patients, 501 cases developed LM. The result of multivariate logistic regression analyses indicated that histologic type, tumor grade, T stage, N stage, lung metastasis, bone metastasis, and tumor size were independent predictive factors for LM in patients with CRNENs (p < 0.05). Multivariate Cox regression analyses indicated that age, primary tumor site, histologic type, tumor grade, N stage, tumor size, chemotherapy, and surgery were independent prognostic factors (p < 0.05) for patients with LM-CRNENs. The predictive and prognostic nomogram models were established based on the independent factors of logistic and Cox analyses. The nomogram models can provide higher accuracy and efficacy in predicting the probability of LM in patients with CRNENs and the prognosis of patients with LM.

The factors associated with the occurrence of LM in CRNENs were identified. On the other hand, the relevant prognostic factors for patients with LM-CRNENs were also demonstrated. The nomogram models, based on independent factors, demonstrate greater efficiency and accuracy, promising to provide clinical interventions and decision-making support for patients.

Rectal neuroendocrine neoplasms (rNENs) are among the most frequent gastrointestinal neuroendocrine neoplasms and pose a serious challenge for clinical management. The size of the primary neoplasm is considered to be the most important predictor of disease progression, but the genetic alterations that occur during the progression of rNENs remain unknown. Here, we performed a comprehensive whole-exome sequencing study on 54 tumor-normal paired, formalin-fixed paraffin-embedded specimens from patients locally diagnosed with rNENs. Of these, 81.5% (n = 44) were classified as small-sized (≤2 cm) rNENs, while the remainder (18.5%, n = 10) were classified as large-sized (>2 cm) rNEN samples. Comparative analysis revealed marked disparities in the mutational landscape between small- and large-sized rNEN samples, and between large-sized rNEN samples with or without lymph node metastases. The high-confidence driver genes RHPN2, MUC16, and MUC4 were significantly mutated in both small- and large-sized rNEN specimens, whereas mutations in MAN2A1, and BAG2 were only identified in large-sized specimens diagnosed with lymph node metastases. Correspondingly, we observed that the mTOR and MAPK pathways were preferentially enriched in the large-sized rNEN specimens. Signature-based analysis revealed that mutational processes associated with defective DNA base excision repair (SBS30) significantly accumulated in large-sized rNEN samples with lymph node metastases, highlighting the important role of this mutagenic process in promoting rNEN progression. We further found that most rNEN subjects, regardless of tumor size, harbored at least one alteration with targeted therapeutic implications. Taken together, these results elucidate the genetic features associated with tumor size and lymphatic metastasis in rNEN patients, which will deepen our understanding of the genetic changes during rNEN progression and potentially directing improvements in rNEN treatment strategies.

Endoscopic therapy (ET) and surgical resection (SR) are common surgical methods for the treatment of colorectal neuroendocrine tumors (CRNETs). However, for elderly patients, it remains unclear which surgical method yields better long-term outcomes.

Elderly patients ≥ 65 years with CRNETs diagnosed from 2000 to 2020 were identified from the Surveillance, Epidemiology, and End Results database. Propensity score matching (PSM) was used to minimize selection bias. The Kaplan-Meier method and Cox proportional hazards models were utilized to evaluate the effects of diverse demographic and clinical factors on overall survival (OS) and cancer-specific survival (CSS).

A total of 2214 patients were included in the study, with 1417 patients in the ET group and 797 patients in the SR group. After PSM, the ET group outperformed the SR group in terms of OS (hazard ratio [HR] 0.56, 95% confidence interval [CI] 0.44-0.70) and CSS (HR 0.21, 95% CI 0.11-0.40). Similarly, the ET group maintained its advantage in mean 1-, 3-, and 5-year OS and CSS rates compared to the SR group (P < 0.001). Multivariate Cox regression analysis identified age, sex, grade, marital status, and treatment modality as independent risk factors affecting OS, while age, sex, marital status, and treatment modality were identified as independent risk factors affecting CSS.

ET offered superior long-term outcomes for elderly patients ≥ 65 years with CRNETs.

Rectal neuroendocrine neoplasms (NENs) are increasing in incidence. Most lesions are low grade, well-differentiated neuroendocrine tumours with good long term outcomes. However there is metastatic potential and resection offers the only option for a cure and in most cases should be offered to reduce the risk of metastases. Careful staging of rectal NENs should be performed prior to consideration of resection in order to ensure the appropriate technique is chosen, and reduce the risk of incomplete resection. Resection can be endoscopic or surgical, and selecting the appropriate resection technique relies on tumour characteristics such as size, grade, invasion into the muscularis propria, presence of lymph node involvement or of distal metastases. Some patients may require systemic therapies which may involve somatostatin analogues (SSAs), everolimus, tyrosine kinase inhibitors (TKIs), chemotherapy or peptide receptor radionuclide therapy (PRRT). Due the rarity of these tumours, much of the evidence is based on retrospective reviews or smaller cohort studies. This article is an update of the current evidence available to guide management.

Colorectal neuroendocrine tumors (NETs) differ significantly from colorectal carcinoma (CRC) in terms of treatment strategy and prognosis, necessitating a cost-effective approach for accurate discrimination. Here, we propose an approach for distinguishing between colorectal NET and CRC based on pathological images by utilizing pathological prior information to facilitate the generation of robust slide-level features. By calculating the similarity between morphological descriptions and patches, our approach selects only 2% of the diagnostically relevant patches for both training and inference, achieving an area under the receiver operating characteristic curve (AUROC) of 0.9974 on the internal dataset, and AUROCs of 0.9724 and 0.9513 on two external datasets. Our model effectively identifies NETs from CRCs, reducing unnecessary immunohistochemical tests and enhancing the precise treatment for patients with colorectal tumors. Our approach also enables researchers to investigate methods with high accuracy and low computational complexity, thereby advancing the application of artificial intelligence in clinical settings.

Endoscopic Submucosal Dissection (ESD) has been reported as a feasible and effective treatment for Rectal Neuroendocrine Tumours (R-NETs). However, most of the experience on the topic comes from retrospective tertiary centre from Eastern Asia. Data on ESD for R-NETs in Western centres are lacking.

This is a retrospective study, including patients who underwent endoscopic resection of R-NETS by ESD between 2015 and 2020 in Western Centres. Important clinical variables such as demographic, size of R-NETs, histological type, presence of lymphovascular invasion or distant metastasis, completeness of the endoscopic resection, recurrence, and procedure related complications were recorded.

40 ESD procedure on R-NETs from 39 patients from 8 centres were included. Mean R-NETs size was 10.3 mm (SD 4.01). Endoscopic en-bloc resection was achieved in 39/40 ESD (97.5 %), R0 margin resection was obtained in 87.5 % (35/40) of the procedures, one patient was referred to surgery for lymphovascular invasion, two procedures (5 %) reported significant episodes of bleeding, whereas a perforation occurred in one case (1/40, 2.5 %) managed endoscopically. Recurrence occurred in 1 patient (2.5 %).

ESD is an effective and safe treatment for R-NETs in western centres.

The identification of risk factors for regional lymph node (r-LN) metastasis in rectal neuroendocrine tumors (R-NETs) remains challenging. Our objective was to investigate the risk factors associated with patients diagnosed with R-NETs exhibiting r-LN metastasis.

Patient information was obtained from the Surveillance, Epidemiology, and End Results (SEER) database, complemented by data from the West China Hospital (WCH) databases. The construction cohort comprised patients diagnosed with R-NETs from the SEER database, while cases from the WCH database were utilized as the validation cohort. A novel nomogram was developed to predict the probability of r-LN metastasis, employing a logistic regression model.

Univariate analysis identified four independent risk factors associated with poor r-LN metastasis: age (HR = 1.027, p < 0.05), grade (HR = 0.010, p < 0.05), T stage (HR = 0.010, p < 0.05), and tumor size (HR = 0.005, p < 0.05). These factors were selected as predictors for nomogram construction.

The novel nomogram serves as a reliable tool for predicting the risk of r-LN metastasis, providing clinicians with valuable assistance in identifying high-risk patients and tailoring individualized treatments.

Interval cancer (IC) is an important quality indicator in colorectal cancer (CRC) screening. Previously, we found that fecal immunochemical test (FIT) ICs are more common in women, older age, right-sided tumors, and advanced stage. Here, we extended our existing stage IV patient cohort with clinicopathological and molecular characteristics, to identify factors associated with FIT-IC.

Logistic regression models were fit to identify variables associated with the odds of having a stage IV FIT-IC. Multivariate models were corrected for gender, age, and location.

A total of 292 screen-detected (SD) CRCs and 215 FIT-IC CRCs were included. FIT-IC CRC had 5 fold higher odds to be a neuroendocrine (NET) tumor and 2.5 fold higher odds to have lymphovascular invasion. Interestingly, some variables lost significance upon accounting for location. Thus, tumor location is a critical covariate that should always be included when evaluating factors related to FIT-IC.

We identified NETs and lymphovascular invasion as factors associated with increased odds of having a stage IV FIT-IC. Moreover, we highlight the importance of tumor location as a covariate in evaluating FIT-IC related factors. More research across all stages is needed to clarify how these insights might help to optimize the Flemish CRC screening program.

Current guidelines recommend endoscopic resection for rectal neuroendocrine tumors (RNETs) under 10 mm. Incomplete resections necessitate salvage procedures, highlighting the need for complete R0 resection. This study evaluates the efficacy and safety of wide hot snare polypectomy (WHSP) compared to endoscopic submucosal dissection (ESD) and endoscopic mucosal resection (EMR) for the salvage treatment of small RNETs.

This retrospective study was conducted at Korea University Guro Hospital from January 2018 to December 2022. It compared the outcomes of salvage resections for RNETs ≤10 mm using 2 approaches: ESD and EMR vs. WHSP. Demographics, tumor characteristics, and clinical outcomes were compared. Efficacy was evaluated by the histological complete resection rate and procedure time, while safety was assessed by the incidence of complications.

Out of 135 patients undergoing salvage resection for RNET, 14 who underwent transanal excision were excluded. Of the remaining 121, 99 underwent EMR or ESD, and 22 underwent WHSP. Baseline characteristics were similar between the 2 groups. The WHSP group demonstrated a significantly higher R0 resection rate (72.7% vs. 49.5%, P = 0.010) and a shorter median procedure time (3.5 minutes vs. 8.3 minutes). No complications were reported in the WHSP group.

WHSP is a rapid, straightforward, safe, and effective approach for the salvage treatment of RNETs less than 10 mm in diameter, particularly in patients without additional risk factors.

The incidence of rectal neuroendocrine tumors (R-NETs) has increased in recent years. However, the predictors of lymph node (LN) metastasis and clinical outcomes, particularly following endoscopic treatment, remain unclear. Our study aims to elucidate the potential risk factors for LN metastasis and the clinical outcomes of patients undergoing endoscopic resection in R-NETs.

A total of 128 patients with R-NETs were retrospectively identified from a single center between June 2012 and December 2021. Risk factors for LN metastasis in R-NETs were analyzed using multivariate analysis. Additionally, the clinical outcomes of endoscopic resections in patients with R-NETs were assessed.

In our study, 128 patients with R-NETs were retrospectively analyzed. The risk factors for LN metastasis determined by multivariate analysis were tumor size and patient age at diagnosis. Among the 111 patients treated with endoscopic resection and with tumor margin records available, 92 underwent endoscopic submucosal dissection (ESD) and 19 underwent conventional endoscopic mucosal resection (EMR). There was no significant difference between the two groups regarding the positive rates of basal tumor margin and lateral tumor margin. Furthermore, 64 patients who underwent endoscopic resection for R-NETs were successfully followed up (range, 1.64-76.71 months), during which only one patient developed local recurrence.

Tumor size and age at diagnosis were predictors for LN metastasis of R-NETs. Both ESD and EMR are alternative techniques with a favorable prognosis for R-NETs, even in cases with positive resection margins. However, due to the relatively small number of patients undergoing EMR and missing data in follow-up protocols, definitive conclusions require further large-scale studies.

Rectal neuroendocrine tumors (rNENs) are rare, constituting 1-2% of rectal tumors, and are often asymptomatic, leading to challenges in early diagnosis. Current management guidelines recommend endoscopic resection for small lesions and surgical intervention for larger or high-risk tumors. This study aims to retrospectively analyze the pathological characteristics, management, and prognosis of rNEN patients.

Data from the Neuroendocrine Tumor Registry at a tertiary hospital in Milan, Italy from 2005 to 2023 were retrospectively analyzed. Patient demographics, disease characteristics, pathology findings, treatment details, and surveillance data were collected. Statistical analyses included descriptive statistics, multivariable binary logistic regression, and Kaplan-Meier survival analysis.

Forty-five patients were included, 53.3% male with a mean age of 57.5 years. Most patients were asymptomatic, with incidental diagnosis during colonoscopy. Endoscopic excision was the primary treatment modality (77.8%), with surgical resection reserved for incomplete or inappropriate endoscopic resections. Disease progression occurred in 13 patients (28.9%), with tumor-related mortality of 22.2%. Kaplan-Meier analysis showed 5- and 10-year survival rates of 68.8% and 59.1%, respectively, with corresponding progression-free survival rates of 72.8% and 54.0%. Tumor stage was significantly associated with disease progression on multivariable analysis (OR = 7.230, p = 0.039).

This study highlights the heterogeneous presentation and prognosis of rNENs, with a substantial proportion diagnosed incidentally. Endoscopic management was predominantly utilized, aligning with current guidelines for localized tumors. Tumor stage emerged as a significant predictor of disease progression, emphasizing the importance of accurate staging for optimal management. Further research is warranted to refine management protocols and validate these findings.

Owing to the lack of evidence-based medical studies with large sample sizes, the surgical approach for the radical resection of rectal neuroendocrine tumors remains controversial.

We retrospectively collected the medical records of patients with rectal neuroendocrine tumors who underwent radical resection at 17 large tertiary care hospitals in China between January 1, 2010, and April 30, 2022. All patients were divided into laparoscopic and open surgery groups. After propensity score matching to reduce confounders, the postoperative and oncologic outcomes were compared between the groups.

We enrolled 174 patients with rectal neuroendocrine tumors who underwent radical surgery. After random matching, 124 patients were included in the comparison (62, laparoscopic surgery group; 62, open surgery group). The laparoscopic surgery group had fewer complications (14.5% vs. 35.5%, P = 0.007) and superior relapse-free survival (P = 0.048). Subgroup analysis revealed that the laparoscopic surgery group had fewer complications (10.9% vs. 34.7%, P = 0.004), shorter postoperative hospital stays (9.56 ± 5.21 days vs. 12.31 ± 8.61 days, P = 0.049) and superior relapse-free survival (P = 0.025) in the rectal neuroendocrine tumors ≤ 4 cm subgroup.

Laparoscopic surgery was associated with improved postoperative outcomes and oncologic prognosis for patients with rectal neuroendocrine tumors ≤ 4 cm; it can serve as a safe and feasible option for radical surgery of rectal neuroendocrine tumors.

Guidelines suggest endoscopic resection for rectal neuroendocrine tumors (rNETs) < 10 mm, but the most appropriate resection technique is unclear. In real-life clinical practice, the endoscopic removal of unrecognized rNETs can take place with "simple" techniques and without preliminary staging. The aim of the current study is to report our own experience at a referral center for both neuroendocrine neoplasms and endoscopy.

Retrospective analyses of polypectomies were performed at the Humanitas Research Hospital for rNETs (already diagnosed or previously unrecognized).

A total of 19 patients were included, with a median lesion size of 5 mm (range 3-10 mm). Only five lesions were suspected as NETs before removal and underwent endoscopic ultrasound (EUS) before resection, being removed with advanced endoscopic techniques. Unsuspected rNETs were removed by cold polypectomy in eleven cases, EMR in two, and biopsy forceps in one. When described, the margins were negative in four cases, positive in four (R1), and indeterminate in one. The median follow-up was 40 months. A 10 mm polypoid lesion removed with cold snare polypectomy (G2 R1) needed subsequent surgery. Eighteen patients underwent EUS after a median time of 6.5 months from resection. The EUS identified local recurrence after 14 months in a 7 mm polypoid lesion removed with cold snare polypectomy (G1 R1); the lesion was treated with cap-assisted EMR. For all the other lesions, the follow-up was negative.

When rNETs are improperly removed without prior staging, caution must be exercised. The data from our cohort suggest that even if inappropriate resection had happened, patients may be safely managed with early EUS evaluation.

 Although endoscopic resection is an effective treatment of rectal neuroendocrine neoplasms (R-NENs) with low malignant potential, there is no consensus on the most recommended endoscopic method. This study aimed to assess the efficacy and acceptability of different endoscopic treatments for R-NENs with low malignant potential.

 We searched databases for studies on treatments of R-NENs using endoscopic resection. These studies comprised techniques such as endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), modified endoscopic mucosal resection (EMRM), modified endoscopic submucosal dissection (ESDM), and transanal endoscopic microsurgery (TEM). The primary outcomes assessed were histological complete resection (HCR).

 Overall, 38 retrospective studies (3040 R-NENs) were identified. Endoscopic mucosal resection with a cap (EMRC), endoscopic mucosal resection with ligation (EMRL), ESD, ESDM, and TEM demonstrated higher resectability than did EMR in achieving HCR. Endoscopic mucosal resection, EMRC, EMRL, EMRP, EMRD, and EMRU required shorter operation times than did ESD. Endoscopic mucosal resection, EMRC, ESDM, and TEM incurred lower risks than did ESD.

 Regarding R-NENs <20 mm with low malignant potential, ESD could be used as the primary treatment. However, TEM may be more effective if supported by economic conditions and hospital facility. With respect to R-NENs <16 mm with low malignant potential, EMRL could be used as the primary treatment. In regard to R-NENs <10 mm with low malignant potential, EMRL, EMRC, and ESD could be used as the primary treatment. However, EMRL and EMRC might be better when operational difficulties and economic conditions were considered.

No consensus regarding the optimal endoscopic resection approach for rectal neuroendocrine tumors (R-NETs) measuring 10-20 mm, this study aims to investigate this issue.

Patients with R-NETs underwent either endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD). The primary endpoint was the complete resection rate, and the secondary endpoints were surgery-related complications and long-term outcomes.

96 patients met the inclusion criteria, 84 patients completed endoscopic resection, and 5 patients were excluded. 79 patients were enrolled and divided into EMR (n = 21) and ESD groups (n = 58). 100% of ESD excisions reached the primary endpoint, while 90.5% of EMR. Endoscopic submucosal dissection can achieve higher R0 rate and lower positive margin rate than EMR. The mean operative time of ESD and EMR was 35.22 ± 8.96 min and 13.14 ± 3.26 min, respectively. The complication rates of ESD and EMR were 3.4% and 4.8%, respectively. For R-NETs between 10 mm and 20 mm, the R0 rate of ESD was significantly higher than that of EMR (100% vs 71.4%, P = .01) and the margin positive rate of ESD was significant lower than that of EMR (4.8% vs 42.9%, P < .05). Both ESD and EMR obtained 100% R0 resection of less than 10 mm R-NET. The median follow-up was 13 months (3-84 months); 1 patient relapsed 25 months after EMR and was re-treated with ESD.

For R-NETs with a diameter less than 10 mm, both EMR and ESD were safe and effective and EMR is convenient and fast, with advantages. ESD offers superiority for R-NETs between 10 and 20 mm and can be considered as the preferred method.

Rectal neuroendocrine tumours (rNETs) are rare but are increasing in incidence. Current management and surveillance recommendations are based on low-grade evidence. Follow-up practices are often inconsistent and costly. This retrospective study analyses a single-centre's experience with rNETs to assess incidence, management practices, outcomes, and guideline adherence.

This is a single-centre retrospective study from Queensland Australia, spanning from 2012 to 2023. Twenty-eight rNET cases met inclusion criteria. Examined parameters included incidence, management, outcomes and adherence to European Neuroendocrine Tumour Society (ENETS) guidelines. R1 resection rate was analysed for associations with resection technique and lesion recognition and recurrence rate was assessed in all patients.

This study shows an increasing incidence of rNETs during the study period, reflecting a global trend. R1 resection rate at initial endoscopy was 75%. There was a general lack of advanced endoscopic techniques utilized and poor lesion recognition, however a statistically significant correlation was not established between these factors and an R1 result (P < 0.05). Most patients with an R1 result had subsequent re-resection to render the result R0, however five patients (33%) underwent surveillance with no reports of recurrence on follow-up. Overall, follow-up practices in our cohort were inconsistent and did not adhere to guidelines.

rNETs are increasing in incidence, emphasizing the need for standardized management and surveillance. Further training is required for rNET recognition and advanced endoscopic resection techniques. Further research is required to assess long-term outcomes in surveilled R1 cases, understand optimal endoscopic resection techniques and further develop local surveillance guidelines.

Purpose: Somatostatin receptor imaging with 18F-AlF-NOTA-octreotide (18F-AlF-OC) has shown promising performance in neuroendocrine neoplasms (NENs). In this study, we aim to investigate the diagnostic performance and clinical impact of 18F-AlF-OC in a large prospective cohort of patients with NEN. Methods: Between January 2023 and November 2023, a total of 219 patients with confirmed or suspected NEN were enrolled prospectively and underwent 18F-AlF-OC PET/CT at 2 h post-injection. The primary endpoint was the diagnostic performance, including sensitivity, specificity, and accuracy. An additional primary endpoint was the impact of 18F-AlF-OC on clinical management. The reference standard was based on the results of histopathology or radiological follow-up. Results: 205 patients were included in the final analysis. The patient-level sensitivity, specificity, and accuracy of 18F-AlF-OC PET/CT compared with contrast-enhanced CT/MRI were 90.5% vs. 81.8%, 93.1% vs. 71.1%, and 91.2% vs. 79.4%, respectively. 26 patients had tiny gastrointestinal NENs (smaller than 1 cm in diameter). The patient-based sensitivity of 18F-AlF-OC PET/CT and contrast-enhanced CT/MRI were 61.5% (16/26) and 37.5% (9/24), respectively. The smallest diameter of gastrointestinal NEN detected by 18F-AlF-OC PET/CT was 0.6 cm in the rectum, 0.3 cm in the stomach, and 0.5 cm in the duodenum. 18F-AlF-OC PET/CT results led to changes in clinical management in 19.5% of patients (40/205), owing mainly to new or unexpected findings compared to contrast-enhanced CT/MRI. Conclusion: 18F-AlF-OC PET/CT demonstrated great diagnostic performance in patients with NEN, particularly for detecting tiny gastrointestinal NEN. Furthermore, 18F-AlF-OC PET/CT impacted the therapeutic management in 19.5% of patients. Our results further validate the role of 18F-AlF-OC as a somatostatin receptor imaging tracer in clinical practice.

Rectal neuroendocrine tumors (RNETs) are often discovered on screening colonoscopy. Indications for staging and definitive resection are inconsistent in current guidelines. We evaluated the role of grade in guiding staging and procedural decision-making.

Patients with biopsy confirmed RNETs between 2004 and 2015 were reviewed. Baseline characteristics, staging investigations (biochemical and imaging), and endoscopic/surgical treatment were recorded. Associations between grade, preoperative staging, interventions, and survival were determined using Fisher-Freeman-Halton Exact, log-rank, and Kaplan-Meier analysis.

Amongst 139 patients with RNETs, 9% were aged ≥ 75 years and 44% female. Tumor grade was: 73% grade 1 (G1), 18%, grade 2 (G2) and 9% grade 3 (G3). Staging investigations were performed in 52% of patients. All serum chromogranin A and 97% of 24-hour urine 5-hydroxyindoleacetic acid tests were normal. The large majority of staging computed tomography (CT) scans were negative (76%) with subgroup analysis showing no G1 patients with CT identified distant disease compared with 38% of G2 and 50% of G3 patients (p < 0.001). G1 patients were more likely to achieve R0/R1 resections compared to G2 (95% vs. 50%, p < 0.001) and G1 patients had significantly better 5-year overall survival (G1: 98%, G2: 67%, G3: 10%, p < 0.001).

Tumor grade is important in preoperative workup and surgical decision-making. Biochemical staging may be omitted but staging CT should be considered for patients with grade ≥ 2 lesions. Anatomic resections should be considered for patients with grade 2 disease.

The present paper reflects the position of the Italian Association for Neuroendocrine Tumors (Itanet), the Italian Society of Gastroenterology (SIGE), and the Italian Society of Digestive Endoscopy (SIED) regarding the management of patients affected by gastric, duodenal, and rectal neuroendocrine neoplasms (NENs) amenable to endoscopic treatment. The key questions discussed in this paper are summarized in Table 1. Data were extracted from the MEDLINE database through searches; expert opinions and recommendations are provided in accordance with the available scientific evidence and the authors' expertise. Recommendations are presented alongside a level of evidence and grade of recommendation based on the GRADE system. This paper specifically focuses on subgroups of NENs considered suitable for endoscopic management according to current international guidelines: i. well-differentiated gastric neuroendocrine tumors (gNET) type 1 < 2 cm and selected cases of type 3; ii. well-differentiated duodenal, non-functioning, non-ampullary NET with size < 2 cm; and well-differentiated rectal NET with size < 2 cm.

Currently, the primary treatment modalities for colorectal neuroendocrine tumors (CRNET) with a diameter between 10mm and 20mm are surgical resection (SR) and endoscopic resection (ER). However, it remains unclear which surgical approach yields the greatest survival benefit for patients.

This study included data from patients diagnosed with CRNET with tumor diameters ranging from 10mm to 20mm between the years 2004 and 2019, obtained from the Surveillance, Epidemiology, and End Results (SEER) database. Patients were categorized into ER and SR groups based on the respective surgical approaches. Inverse probability weighting (IPTW) was employed to mitigate selection bias. Kaplan-Meier analysis and log-rank tests were utilized to estimate overall survival (OS) and cancer-specific survival (CSS). Cox regression analysis (univariate and multivariate) was performed to evaluate potential factors influencing survival.

A total of 292 CRNET patients were included in this study (ER group: 108 individuals, SR group: 184 individuals). Prior to IPTW adjustment, Kaplan-Meier analysis and Cox proportional hazard regression analysis demonstrated that the OS and CSS of the SR group were inferior to those of the ER group. However, after IPTW adjustment, no statistically significant differences in prognosis were observed between the two groups. Subgroup analyses revealed that patients with muscular invasion, positive lymph nodes, or distant metastasis derived greater survival benefits from SR. Significant differences in OS and CSS between the two groups were also observed across different age groups.

For patients with mucosal-limited lesions and without local lymph node or distant metastasis, ER is the preferred surgical approach. However, for patients with muscular invasion or positive lymph nodes/distant metastasis, SR offers a better prognosis. The choice of surgical approach should be based on the specific clinical characteristics of patients within different subgroups.

The efficacy and safety of local excision (LE) for small (< 1‒2 cm) colonic neuroendocrine tumors (NETs) is controversial due to the higher metastasis risk when compared with rectal NETs. The study aimed to evaluate the metastasis risk of T1 colonic NETs and compare patients' long-term prognosis after LE or radical surgery (RS).

The Surveillance Epidemiology and End Results database was used to identify patients with T1 colonic NETs (2004‒2015). Multivariable logistic regression was performed to assess factors associated with metastasis risk. Propensity score matching was used to balance the variables. Cancer-specific survival (CSS) and overall survival (OS) were calculated to estimate the prognosis of patients with T1N0M0 colonic NETs who underwent LE or RS.

Of the 610 patients with colonic NETs, 46 (7.54%) had metastasis at diagnosis. Tumor size (11-20 mm) (OR = 9.51; 95% confidence interval (CI): 4.32‒21.45; P < 0.001), right colon (OR = 15.79; 95% CI 7.20‒38.56; P < 0.001), submucosal infiltration (OR = 2.08; 95% CI 0.84‒5.57; P = 0.125) were independent risk factors associated with metastasis. Of the 515 patients with T1N0M0 colonic NETs, the overall long-term prognosis of LE was as good as that of RS groups (after matching, 5-year CSS: 97.9% vs. 94.6%, P = 0.450; 5-year OS: 92.7% vs. 85.6%, P = 0.009).

Tumor size (11‒20 mm) and site (right colon) are associated with metastasis in T1 colonic NETs. In the absence of metastasis, LE could be a viable option for 0‒10 mm T1 colonic NETs with well/moderate differentiation in the left colon in terms of long-term survival.

Conventional endoscopic mucosal resection (cEMR), EMR with a transparent cap, EMR using a ligation device (EMR-L), EMR after circumferential precutting (EMR-P), and endoscopic submucosal dissection (ESD) have been used for resecting rectal neuroendocrine tumors (r-NETs). However, there is no consensus regarding which is the best treatment. This study aimed to compare the outcomes of the aforementioned 5 techniques for resecting r-NETs by network meta-analysis.

Electronic databases (PubMed, Cochrane Library, Embase, Ovid Medline, and Web of Science) were systematically searched to include relevant studies published from inception to September 1, 2023. The en bloc resection rate, histologic complete resection rate, positive lateral margin rate, positive vertical margin rate, adverse events rate, and procedure time were compared.

A total of 27 studies with a total of 2112 r-NETs were included, and the mean diameter of tumors was 6.24 mm. Pairwise meta-analysis showed that EMR-L and ESD had higher en bloc resection and histologic complete resection rates and lower positive vertical margin rate than those of cEMR in resecting r-NETs. Compared with ESD, EMR-L and EMR-P achieved similar resection rates and significantly shortened the procedure time without increasing adverse events. The network meta-analysis evaluated the surface under the cumulative ranking curves and revealed that EMR-L was the best modality for treating r-NETs considering the comprehensive results of the en bloc resection rate, histologic complete resection rate, positive lateral margin rate, positive vertical margin rate, adverse events rate, and procedure time.

EMR-L should be recommended as the first-line endoscopic treatment for small r-NETs.

Background and Objectives: Gastric neuroendocrine neoplasms (gNENs) represent rare but increasingly recognized tumors. They are distinguished into three main clinical types (type-1, type-2, and type-3) according to gastrin level and at histological evaluation in well-differentiated G1, G2, or G3 lesions, as well as poorly-differentiated lesions. Small type-1 and type-2 neoplasms with low proliferation indices demonstrated excellent survival without progression during an extended follow-up period, and for these reasons, active endoscopic observation or endoscopic resection are feasible options. On the other hand, surgery is the treatment of choice for more aggressive type-3, G3, or infiltrating neoplasms. The present study aims to comprehensively review and compare the available therapeutic strategies for gNENs. Materials and Methods: A computerized literature search was performed using relevant keywords to identify all of the pertinent articles with particular attention to gNEN endoscopic treatment. Results: In recent years, different endoscopic resective techniques (such as endoscopic mucosal dissection, modified endoscopic mucosal resection, and endoscopic full-thickness resection) have been developed, showing a high rate of complete resection for advanced and more aggressive lesions. Conclusions: Overall, gNENs represent a heterogeneous group of lesions with varying behavior which require personalized management. The non-operative approach for small type-1 gNENs seems to be feasible and should be promoted. A step-up approach with minimally invasive endoscopic therapies might be proposed, particularly for type-1 gNEN. On the other hand, it is important to recognize the negative prognostic factors in order to identify those rare cases requiring more aggressive approaches. A possible therapeutic algorithm for localized gNEN management is provided.

While an elevated risk of second primary cancers (SPCs) has been observed in many other cancers, risk of SPCs has not been quantified in patients with rectal neuroendocrine neoplasms (NENs).

Survivors of primary rectal NENs diagnosed between 2000 and 2018 were identified from the Surveillance, Epidemiology, and End Results (SEER)-18 registries. Relative risk of SPCs was estimated as the standardized incidence ratio (SIR), which was calculated using SEER*Stat software.

Between 2000 and 2018, a total of 15836 patients diagnosed with rectal NENs, of whom 1436 (9.1%) received diagnosis of SPCs (SIR: 1.19, 95%CI: 1.13-1.26). The majority of patients were aged 50-69 and had their first cancer diagnosed at the localized stage. Male survivors had a higher propensity for developing SPCs overall, while female survivors exhibited higher risks of specific SPCs. Age at diagnosis of rectal NENs influenced the risk of SPCs, with younger patients having greater risks. A statistically significant increase in the incidence of SPCs was observed among patients aged 30-64 years. Black patients had higher relative risks of certain SPCs, while White patients had a lower risk of subsequent melanoma. Trend analysis revealed that the highest excess burden of SPCs was observed in the years 2000 to 2002. Risk of SPCs remained elevated within the first four years post-diagnosis for survivors of rectal NENs, but diminished thereafter.

The study revealed that individuals who survived rectal NENs were at an elevated risk of developing SPCs compared to the general population. Our results hold important implications for the formulation of lifelong surveillance recommendations for cancer survivors.

Neuroendocrine neoplasms (NENs), also called neuroendocrine tumors (NETs), are relatively uncommon, heterogenous tumors primarily originating in the gastrointestinal tract. With the improvement in technology and increasing use of cross-sectional imaging and endoscopy, they are being discovered with increasing frequency. Although traditionally considered indolent tumors with good prognoses, some NENs exhibit aggressive behavior. Timely diagnosis, risk stratification, and management can often be a challenge. In general, small NENs without local invasion or lymphovascular involvement can often be managed using minimally invasive advanced endoscopic techniques, while larger lesions and those with evidence of lymphovascular invasion require surgery, systemic therapy, or a combination thereof. Ideal management requires a comprehensive and accurate understanding of the stage and grade of the tumor. With the recent advancements, a therapeutic advanced endoscopist can play a pivotal role in diagnosing, staging, and managing this rare condition. High-definition white light imaging and digital image enhancing technologies like narrow band imaging (NBI) in the newer endoscopes have improved the diagnostic accuracy of traditional endoscopy. The refinement of endoscopic ultrasound (EUS) over the past decade has revolutionized the role of endoscopy in diagnosing and managing various pathologies, including NENs. In addition to EUS-directed diagnostic biopsies, it also offers the ability to precisely assess the depth of invasion and lymphovascular involvement and thus stage NENs accurately. EUS-directed locoregional ablative therapies are increasingly recognized as highly effective, minimally invasive treatment modalities for NENs, particularly pancreatic NENs. Advanced endoscopic resection techniques like endoscopic submucosal dissection (ESD), endoscopic submucosal resection (EMR), and endoscopic full-thickness resection (EFTR) have been increasingly used over the past decade with excellent results in achieving curative resection of various early-stage gastrointestinal luminal lesions including NENs. In this article, we aim to delineate NENs of the different segments of the gastrointestinal (GI) tract (esophagus, gastric, pancreatic, and small and large intestine) and their management with emphasis on the endoscopic management of these tumors.

Local resection, including endoscopic resection, is recommended for rectal neuroendocrine tumors (NETs) < 15 mm in patients without risk factors for metastasis, though the short- and long-term outcomes are unclear.

This study investigates the efficacy of endoscopic resection for rectal NETs < 15 mm.

The short- and long-term outcomes of patients with rectal NETs < 15 mm who underwent endoscopic resection and the outcomes of each endoscopic technique were analyzed. The tumors were stratified as < 10 mm (small-size group, SSG) and 10-14 mm (intermediate-size group, IMG).

Overall, 139 lesions (SSG, n = 118; IMG, n = 21) were analyzed. All tumors were classified as G1 (n = 135) or G2 (n = 4) according to the 2019 World Health Organization grading criteria. The complete resection rate was not different between the groups (P = 0.151). Endoscopic submucosal dissection (ESD) and endoscopic submucosal resection with a ligation device (ESMR-L) achieved complete resection rates > 90% in the SSG. The ESMR-L procedure time (P < 0.001) and hospitalized period (P < 0.001) were significantly shorter than those of ESD. ESD achieved a complete resection rate of 80.0% in the IMG. The tumor size did not affect the overall survival or rate of lymph node/distant metastases.

Endoscopic resection is a feasible and effective treatment for patients with rectal NETs < 15 mm without the risk factors of metastasis. ESMR-L and ESD are optimal techniques for resecting tumors smaller than 10 mm and 10-14 mm, respectively.

Rectal neuroendocrine neoplasms are rare epithelial neoplasms of the rectum. The incidence of these tumors has increased over the past decades. However, many questions remain unanswered regarding their clinicopathology, including the possible mechanisms in which these tumors may grow and metastasize.

In this case report, we report the findings of an autopsy of a 65-year-old Japanese woman diagnosed with multiple liver metastases from a single, low-grade rectal neuroendocrine tumor. The diagnosis was made in late 2018 to early 2019, and subsequently the patient underwent several rounds of standard chemotherapy. However, due to unfavorable side effects, she opted for palliative care at our hospital instead from December 2020. The patient's condition was generally stable for the next 17 months, but in May 2022, she was hospitalized for increased abdominal pain. Despite enhanced pain control therapy, she eventually passed away. An autopsy was conducted to determine the exact cause of death. The primary rectal tumor was found to be small, but showed strong histological evidence of venous invasion. Metastases in the liver, pancreas, thyroid gland, adrenal glands, and vertebrae were also present. On the basis of the histological evidence obtained, we deduced that the tumor cells may have mutated and gained multiclonality as they spread vascularly to the liver, contributing to the distant metastases.

The results from this autopsy may provide an explanation for the possible mechanism by which small, low-grade rectal neuroendocrine tumors metastasize.

Gastric neuroendocrine neoplasms (gNENs) are a rare type of gastric neoplasm, even if their frequency is increasing according to the latest epidemiologic revisions of the main registries worldwide. They are divided into three main subtypes, with different pathogeneses, biological behaviors, and clinical characteristics. GNEN heterogeneity poses challenges, therefore these neoplasms require different management strategies. Update the knowledge on the endoscopic treatment options to manage g-NENs. This manuscript is a narrative review of the literature. In recent years, many advances have been made not only in the knowledge of both the pathogenesis and the molecular profiling of gNENs but also in the endoscopic expertise towards innovative treatment options, which proved to be less aggressive without losing the capability of being radical. The endoscopic approach is increasingly applied in the field of gastrointestinal (GI) luminal neoplasms, and this is true not only for adenocarcinomas but also for gNENs. In particular, different techniques have been described for the endoscopic removal of suspected lesions, ranging from classical polypectomy (cold or hot snare) to endoscopic mucosal resection (both with "en bloc" or piecemeal technique), endoscopic submucosal dissection, and endoscopic full-thickness resection. GNENs comprise different subtypes of neoplasms with distinct management and prognosis. New endoscopic techniques offer a wide variety of approaches for GI localized neoplasms, which demonstrated to be appropriate and effective also in the case of gNENs. Correct evaluation of size, site, morphology, and clinical context allows the choice of tailored therapy in order to guarantee a definitive treatment.

The first choice of treatment for rectal neuroendocrine tumors (R-NETs) 10 mm in size is endoscopic resection, there is still controversy concerning the optimal endoscopic treatment for resecting R-NETs. This study evaluated the efficacy and safety of multiple ligation-assisted endoscopic submucosal resection combined with endoscopic ultrasonography (EMR-MLUS) for R-NETs.

We retrospectively analyzed the data of 62 patients with R-NETs ≤10 mm in size who underwent EMR-MLUS or ligation-assisted endoscopic submucosal resection combined with endoscopic ultrasonography (EMR-LUS) between May 2019 and April 2022, including tumor characteristics, endoscopic complete resection, pathological complete resection, the procedure time, adverse events, and follow-up were compared between the two groups of patients.

Of the 62 patients, 19 underwent EMR-MLUS and 43 underwent EMR-LUS. The endoscopic morphology of lesions was statistically different between group EMR-MLUS and group EMR-LUS ( P = 0.015), and most of them were flat and slightly raised lesions in group EMR-MLUS. Although the pathological complete resection rate was slightly higher in the EMR-MLUS group than in the EMR-LUS group (94.74% vs. 90.70%; P = 0.290), the endoscopic complete resection rate was high in both groups. Involvement of the lateral resection margin was found four cases in the ESMR-LUS group; one case of deep resection margin involvement in the EMR-MLUS group. The mean procedure time was longer in the EMR-MLUS group than in the EMR-LUS group (12.79 ± 1.01 min vs. 11.08 ± 1.89 min; P = 0.041). In group EMR-LUS, there were two cases of immediate bleeding; in group EMR-MLUS, one case of perforation, all of them were successfully treated by endoscopy. No recurrence, progression, or metastasis was found in all patients.

EMR-MLUS is a safe and effective technique that could be considered when removing small rectal NETs, especially flat and slightly raised lesions.